Metabolic profiling of maternal serum of women at high-risk of spontaneous preterm birth using NMR and MGWAS approach.

Juhi K Gupta,Zarko Alfirevic,Laura Goodfellow,Angharad Care,Marie M Phelan,Ana Alfirevic,Lu-Yun Lian,Bertram Müller-Myhsok

doi:10.1042/bsr20210759

Abstract

Preterm birth (PTB) is a leading global cause of infant mortality. Risk factors include genetics, lifestyle choices and infection. Understanding the mechanism of PTB could aid the development of novel approaches to prevent PTB. This study aimed to investigate the metabolic biomarkers of PTB in early pregnancy and the association of significant metabolites with participant genotypes. Maternal sera collected at 16 and 20 weeks of gestation, from women who previously experienced PTB (high-risk) and women who did not (low-risk controls), were analysed using 1H nuclear magnetic resonance (NMR) metabolomics and genome-wide screening microarray. ANOVA and probabilistic neural network (PNN) modelling were performed on the spectral bins. Metabolomics genome-wide association (MGWAS) of the spectral bins and genotype data from the same participants was applied to determine potential metabolite-gene pathways. Phenylalanine, acetate and lactate metabolite differences between PTB cases and controls were obtained by ANOVA and PNN showed strong prediction at week 20 (AUC = 0.89). MGWAS identified several metabolite bins with strong genetic associations. Cis-eQTL analysis highlighted TRAF1 (involved in the inflammatory pathway) local to a non-coding SNP associated with lactate at week 20 of gestation. MGWAS of a well-defined cohort of participants highlighted a lactate-TRAF1 relationship that could potentially contribute to PTB.

Highlights

Preterm birth (PTB) is defined by the World Health Organisation as birth prior to 37 weeks of gestation [1]
To provide targeted spontaneous preterm birth (SPTB) preventative therapies, reliable biomarkers of women with pregnancies destined to labour prematurely are required
The present study aimed to investigate the serum metabolome from a unique cohort of high-risk PTB women in early pregnancy using untargeted 1-dimensional 1H nuclear magnetic resonance (NMR)

Summary

Introduction

Preterm birth (PTB) is defined by the World Health Organisation as birth prior to 37 weeks of gestation [1]. Environmental factors are known to influence PTB and include nutrition, maternal stress or infection [1]. Metabolomics is a field that monitors global metabolism of a system, and this can be influenced by both environmental and genetic factors [3,4]. Clinical phenotypes of non-iatrogenic spontaneous labour include spontaneous preterm birth (SPTB) and PPROM (preterm premature rupture of membranes). To provide targeted SPTB preventative therapies, reliable biomarkers of women with pregnancies destined to labour prematurely are required. This can be achieved by understanding the pathophysiology behind the initiation of early labour. Different regulation axis between SPTB and PPROM have previously been suggested [5]

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Conclusion